Chemical Components and Cardiovascular Activities of Valeriana spp.

Valeriana spp. is a flowering plant that is well known for its essential oils, iridoid compounds such as monoterpenes and sesquiterpenes, flavonoids, alkaloids, amino acids, and lignanoids. Valeriana spp. exhibits a wide range of biological activities such as lowering blood pressure and heart rate, antimyocardial ischemia reperfusion injury, antiarrhythmia, and regulation of blood lipid levels. This review focuses on the chemical constituents and cardiovascular activities of Valeriana spp.

The roots and rhizomes of Valeriana spp. are rich in essential oils, iridoids, flavonoids, alkaloids, amino acids, and lignanoids [5][6][7][8][9], which possess characteristic fragrance or off-flavor and are used as medicines based on their inherent bioactivities that include inducing sedation, promoting sleep, antidepression, and antianxiety [10][11][12][13][14][15][16][17][18]. Valeriana spp. is now listed in the European and USA pharmacopeias. It is also sold as a diet supplement in the USA and is one of the highest selling natural medicines in Europe and the USA [19]. In addition, Valeriana spp. is of high medical and economic value in the food, drink, and cosmetic industries due to its distinct flavor, and current research efforts are aimed at further exploiting other features of the plant [20,21]. This review focuses on the chemical constituents and cardiovascular activities of Valeriana spp., aiming at providing a theoretical foundation for further research and evaluation of its medicinal value.

Essential Oils.
Approximately 0.5%-2.0% of Valeriana spp. consists of essential oils by gas chromatography-mass spectrometry (GC-MS), which varies with species, climate, and growing environment. Valerian plants from high-altitude fertile and sandy soil have significantly higher essential oil content and yield similar to that of biennials compared to annuals. Valerian plants that produce a higher amount of essential oil are cultivated between September and November, although the content of essential oils decreases with longer periods of propagation.
A total of 150 compounds have been identified in the essential oils of Valerian plants, mainly including monoterpenes and sesquiterpenes. Most monoterpenes, namely, borneol, bornyl acetate, and isobornyl acetate, exhibit various bioactivities. Around 30 sesquiterpenes have also been detected in the Valerian essential oils. These have been 2 Evidence-Based Complementary and Alternative Medicine  [27], and Yu et al. [28] previously investigated essential oils from Valeriana by GC-MS, showing its content was 1%, and 20%-60% of it was bornyl acetate. Wang et al. [27] detected 34 compounds by GC-MS, which comprised 91.75% of the total content of the essential oil of V. officinalis L. var. latifolia Miq. (Table 1 and Figure 1). Compared to the standard spectrum, bornyl acetate showed the highest content level at 23.93%, followed by nootkatone (14.79%) and 6-isopropyl-1-methyl bicycles [  Cultivated V. officinalis L. var. latifolia Miq. consisted of a higher number of simple components, which was predominated by bornyl acetate relative to that of wild V. officinalis L.

Iridoids.
Valepotriate was first isolated from V. wallichii and preliminary studies by Thies and Funke [29] have confirmed the presence of a sedation ingredient. The study drew the attention of researchers from around the world. To date, over 130 iridoids from Valeriana spp. have been identified, possibly contributing their sedative, antidepressant, and antitumor activities.
Chen et al. [30] studied the levels of valepotriate, dihydrovalepotriate, and acetyl-valepotriate from V. jatamansi Jones, V. officinalis L., and V. officinalis L. var. latifolia Miq. by using the reverse phase high-performance liquid chromatography (RP-HPLC) method. The highest levels were observed in V. jatamansi Jones, followed by V. officinalis L. and V. officinalis L. var. latifolia Miq. In addition, the content of iridoid varied significantly among different parts and habitats.

Diethenoid-Type Iridoids.
Diethenoid-type iridoids were characterized by the following molecular structures: (1) two C-C double bonds often presented between C-3 and Table 2 Number C-4, C-5, and C-6 and occasionally presented between C-4 and C-5, C-6, and C-7; (2) an oxacyclopropane was often presented between C-8 and C-10, and C-10 was usually in a -configuration; (3) H-1 ( -configuration) and H-9 (configuration) were preferentially located on different sides of the ring, and the C-7 acyl group usually was determined to be in the -configuration ( Figure 2 and Table 2 and Figure 3 and Table 3).
Evidence-Based Complementary and Alternative Medicine 5 were mostly of the two above-mentioned types ( Figure 5). In addition, other types were also identified: (1) most of one type having free hydroxyl groups and ester groups, with a lactone structure between C-1 and C-3 and a double bond between C-4 and C-1, (2) an oxygen bridge between C-3 and C-8, C-3 and C-10, or C-8 and C-11, (3) cleaved Ring-A of other types forming a free hydroxyl or aldehyde group between C-1 and C-3 (e.g., see Lin et al. [31]).     Table 4). kaempferol, linarin, and luteolin [10,33,34], which occurred at low levels.

Reduction in Blood Pressure Level and Heart
Rate. The increase of peripheral resistance in blood circulation was the common characteristic for primary hypertension, whose pathological mechanism was related to an increase of peripheral vascular tone and structural change of vessel walls.
Additionally, structure and function disorders of vascular smooth muscle cells (VSMC) also contributed largely to this abnormal change. Therefore, improving the contract status of VSMC, expending the peripheral vessels, and inhibiting abnormal growth of VSMC preventing or alleviating vessel reconstruction at the same time were the keys to treating hypertension. Wang et al. [63] cultured aortic medial smooth muscle cells from a 6-month-old aborted fetus and examined the migration of cultured cells by Boyden Chamber. They found essential oil (VOL) could significantly inhibit the migration of human VSMC in a dose-dependent manner. Yang et al. [64] observed the effect of VOL and L-nitro arginine methyl ester (L-NAME) on the contraction of VSMC through the analogous experiment and investigated changes of 3 H-thymidine ( 3 H-TdR) and 3 H-Leucine caused by angiotensin II (Ang II) and different concentrations of VSMC. VOL markedly inhibited the Ang II-stimulated contraction and growth of VSMC, which was not affected  by L-NAME. In addition, VOL inhibited the incorporation of 3 H-TdR and 3 H-leucine. Zhou et al. [65] found that VOL could decrease the heart rate and blood pressure (priority to diastolic pressure) of rabbit and prolonged the duration of ST segment and T wave in a dose-dependent manner. VOL could decrease heart rate and blood pressure stimulated by adrenaline, which might be related to relaxing VSMC, enlarging vessel diameter, and decreasing blood resistance. VOL also observably inhibited contraction of VSMC stimulated by adrenaline, dilated coronary arteries, and decreased myocardial oxygen consumption. The vasorelaxant effects of the EtOH extract (1 mg⋅mL −1 ) and 8-hydroxypinoresinol (100 m) from the roots of Valeriana prionophylla have been already shown [66]. Fields et al. [66] reported that VOL could dilate pulmonary vessels in felines via a nonselective GABA mechanism and inhibited contraction of isolated frog hearts stimulated by cardenolide. It has already been shown that hexanic extracts (HEVe) from V. edulis ssp. procera enriched in valepotriates present vasorelaxant properties by blocking calcium channels. HEVe induced a significant concentrationdependent and endothelium-independent relaxation on isolated rat aorta precontracted with noradrenaline (0.1 m). HEVe, the most potent extract (0.15-50 g/mL), induced relaxation in aortic rings precontracted with KCl (80 mm), with IC 50 value of 34.61 g/mL and max value of 85.0% [67].

Antimyocardial Ischemia Reperfusion Injury.
As early as the 1980s, Zhang et al. [68] reported that the ethanol extract of valerian could dilate the coronary artery and reduce myocardial oxygen consumption in anesthetized cats. Yang et al. [69] reported that its essential oil and iridoids enhance microcirculation perfusion of the heart and kidney. The valerian extract can prevent injuries to myocardial ischemia reperfusion model in the rabbit by decreasing the levels of xanthine oxidase (XOD), malondialdehyde (MDA), and tumor necrosis factor-(TNF-), thereby increasing the 6-ketoprostaglandin F1 /thromboxane B2 (6-keto-PGF1 /TXB2) ratio. Huang et al. [70] conducted a study to investigate myocardial protection mechanism of monoterpene oxide of valerian (VMO). Compared to the control group, VMO showed a maximum change rate of left ventricular pressure, with a maximal rate of the increase of the left ventricular pressure (+ ip / max ) and maximal rate of the decrease of the left ventricular pressure (− ip / max ) by 25.1% and 25.3%, respectively. Adenosine triphosphate (ATP) and energy charge ( ) increased by 72.8% and 20.9%, respectively, whereas myocardial creatine kinase-myocardial band (CK-MB) decreased by 20.7%. These results demonstrated the analogical performance between VMO and ischemic preconditioning pretreatment on cardio protection, which indicated a mobilizing myocardial endogenesis protective mechanism and an exoteric ATP-sensitive potassium channel. Yang et al. [71] set up an isolated rat ischemia reperfusion (I/R) heart model using a Langendorff-perfusion system, observing the effects of VOL pretreatment on I/R injury and related biochemical factors and cytosolic free calcium. The results indicated that VOL pretreatment markedly prevented I/R injury, weakened vasospasm perfusion, sustained the heartbeat, and reduced ventricular arrhythmic events in a dose-dependent manner. Simultaneously, VOL significantly lowered lactate dehydrogenase (LDH), creatine phosphokinase (CK), and MDA levels. The activities of superoxide dismutase (SOD), adenosine triphosphatase (ATPase), and glutathione peroxidase (GSH-Px) were enhanced. VOL reduced intracellular calcium in a concentration-dependent manner. The mechanism of action for VOL's aforementioned activities potentially involved preventing the increase in concentration of free Ca 2+ and decrease in lipid peroxidation.

Antiarrhythmia.
Arrhythmia is a common disease that involves various pathological mechanisms. Although western medicines have considerable efficiency, the adverse reactions at different levels and the development of arrhythmia caused by the drug itself have been reported. Therefore, it is imperative to discover an antiarrhythmic drug that features efficiency, stability, and the absence of adverse effects; these properties are inherent to traditional Chinese medicine, which are also of scientific and societal significance. Arrhythmia induced by aconitine might be caused by myocardium excitability, which opens Na + channel of the cardiac muscle and promotes sodium currents, resulting in a ventricular and supraventricular ectopic rhythm and ventricular tachycardia. Ventricular fibrillation induced by chloroform could be related to the release of neurotransmitters or adrenaline secretion in the adrenal medulla, as well as stimulation of receptors [72,73].
Jia and Zhang [74] found that chloroform extract of ethanol extract (v3d) could effectively prevent atrial fibrillation in mice induced by acetylcholine-calcium chloride and ventricular fibrillation induced by chloroform. It also protected rats from ischemia arrhythmia induced by ligation of the left anterior descending coronary artery. In addition, it effectively prevents dog auricular and renal vessels contraction induced by high K + levels. Therefore, v3d prevents arrhythmia in various animal species partly by inhibiting Ca 2+ channel from opening, which was induced by high K + level.
Huang [75] found valerian extract (monoterpene and sesquiterpene oxides from essential oils) could dose-dependently reduce the duration of an action potential and inhibit 8 Evidence-Based Complementary and Alternative Medicine Na current ( Na ), L-type calcium current ( Ca-L ), and transient outward potassium current ( to ). It interacts with inactivated Na and Ca-L , although various concentrations of v3d had no detectable effect on the delayed rectifier potassium current ( K ) or inward rectifier potassium current ( KI ) or direct interference with adenosine triphosphate sensitive potassium current ( KATP ). The impacts of the valerian extract on these ion pathways might have contributed to its antiarrhythmia activity.
Wen et al. [76] reported the water, essential oil, and other fractions of valerian could protect a rat model from arrhythmia caused by aconitine or chloroform. Water extract at a dose of 50 and 25 g⋅kg −1 (calculated as raw herb) effectively decreased the occurrence of ventricular fibrillation, delayed the occurrence of arrhythmia, and decreased the mortality rate. The essential oil at a dose of 50 and 25 g⋅kg −1 (calculated as raw herb) effectively inhibited arrhythmia that was induced by chloroform; other fractions also demonstrated antiarrhythmia activities at different levels. Duan [77] found two active compounds from V. officinalis L., prinsepiol-4-O--D-glucoside and 8-hydroxy pinoresinol-4-O--D-glucoside; both showed antiarrhythmia activities. The former imparted an inhibitory effect on the Kv1.5 channel, which is the key mechanism for antiarrhythmia activity.
It was shown that didrovaltrate blocks L-type calcium current in a concentration-dependent manner and probably inhibited these currents in its inactive state. Didrovaltrate at concentrations of 30 g/L and 100 g/L significantly decreased peak Ca-L ( Ca-Lmax ) from 6.01 to 3.45 pA/pF and 2.16 pA/pF, respectively. Didrovaltrate shifted upwards the current-voltage curves of Ca-L without changing their active, peak, and reverse potentials. Didrovaltrate affected the steady-state inactivation of Ca-L . The half activation potential ( 1/2 ) was significantly shifted from −26 to −36 mV, with a significant change in the slope factor ( ) (from 8.8 to 11.1) [78].
Liu et al. [79] studied antiarrhythmia effective substances in serum of V. officinalis L. The study showed that borneol and bornyl acetate from Valerian essential oils and another unidentified compound from ethyl acetate extract could be absorbed into the blood in its original form, which indicated that this unidentified compound might be the main substance that contributes to the antiarrhythmia activity of the ethyl acetate extract.

Regulation of Blood Lipid Levels.
Reports on V. officinalis L. var. latifolia Miq. (VOL) and its constituents in lipid regulation are limited. Hu et al. [80] examined the effects of VOL on blood lipid metabolism in rabbits with hyperlipidemia. VOL imparts a remarkable antilipid peroxidation effect, reduces the levels of serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and MDA, and elevates the levels of high-density lipoprotein cholesterol (HDL-C) and SOD. The results prove that it is imperative to further investigate the underlying mechanisms in regulating lipid metabolism. Si et al. [81] also demonstrated VOL could reduce the serum levels of total cholesterol, low-density lipoprotein, urinary albumin, and serum creatinine. Light microscopy and immunohistochemical stain revealed that, in the same time of lowering serum lipid, mesangial matrix index was significantly reduced, accompanied by decreased expression of TGF-1 and type IV collagen.

Conclusions
Valeriana spp. possesses a wide range of bioactivities, which have been conferred by its complex and diverse active ingredients. Although the effects of Valeriana spp. mainly affected the cardiovascular system in Section 3, its mechanism of action needs to be further investigated.